Inflammasomes: too big to miss Andrea Stutz, … , Douglas T. Golenbock, Eicke Latz J Clin Invest. 2009;119(12):3502-3511. https://doi.org/10.1172/JCI40599. Science in Medicine Inflammation is the coordinated immune response to harmful stimuli that appear during infections or after tissue damage. Cells of the innate immune system are the central players in mediating inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mechanisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed “inflammasomes,” which regulate the activity of caspase-1 and the maturation and release of IL-1β. Find the latest version: https://jci.me/40599/pdf Science in medicine Inflammasomes: too big to miss Andrea Stutz,1 Douglas T. Golenbock,1 and Eicke Latz1,2 1Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 2Institute of Innate Immunity, University of Bonn, Bonn, Germany. Inflammation is the coordinated immune response to harmful stimuli that appear during infec- tions or after tissue damage. Cells of the innate immune system are the central players in mediating inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mecha- nisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed “inflamma- somes,” which regulate the activity of caspase-1 and the maturation and release of IL-1β. Innate immune signaling receptors these signaling receptors can detect a broad variety of molecular orchestrate inflammation entities including lipids, proteins, nucleic acids, and combinations Inflammation is a host response to infectious agents, tissue dam- thereof. While it is likely that innate immune receptors evolved age, or cellular irritants such as toxins. Immune cells encounter- to recognize specific molecules associated with microbes, many of ing these noxious agents become activated and release an array these same receptors can also detect molecular changes that occur of factors leading to the well-known clinical signs of inflamma- during tissue damage. Ligands for innate immune receptors can be tion: rubor, calor, dolor, tumor, and functio laesa. The structured of foreign nature, i.e., not synthesized by the host, such as bacterial inflammatory reactions within the local tissue lead to the recruit- LPS. Additionally, the innate immune system can detect molecules ment of a variety of immune cells, which act in concert with local that are normally sequestered in specific subcellular compart- tissue cells to remove the infectious agent, clear damaged tissue ments and that relocate upon cellular damage, such as the nuclear components, and initiate tissue repair processes. This inflamma- protein HMGB1. Other emerging principles of innate receptor tory response has the effect of protecting the host from further activation are the ability of the host to detect modified self-mole- tissue damage and restoring tissue function. However, under cer- cules that appear under disease conditions, including the response tain conditions, immune responses themselves can injure tissues to certain glycosylated proteins or the recognition of crystalline or result in chronic inflammatory processes. The inflammatory materials, such as may occur in gout (1). Indeed, the scope of the response is the result of the activity of a plethora of cell-derived innate immune system is very large, and our understanding of its mediators (e.g., chemokines, cytokines, antimicrobial peptides, function is likely to expand exponentially in the next few years. and reactive oxygen and nitrogen species) and of activated bio- This review focuses on the mechanisms of activation of a subset of chemical cascades originating in the vascular compartment (e.g., signaling receptors of the NLR family of proteins. complement, coagulation, and fibrinolytic systems). How cells respond to infectious and non-infectious inflamma- NLR proteins and inflammasomes tory stimuli has long been of immense interest. Research in the NLRs are a family of intracellular immune receptors with more field of inflammation and in particular innate immunity has led than 20 members currently known in humans. The NLR family to a more detailed, albeit still fragmentary, understanding of the members are characterized by the presence of at least two shared molecular mechanisms by which many innate immune signaling features, leucine-rich repeats (LRRs) near the C terminus and a receptors activate cells. NACHT nucleotide-binding domain (NBD). The LRR domains of The innate immune system is found in all species of plant and this family are thought to play a role in autoregulation, the recog- animal life and provides the immediate host immune response to nition of pathogen-associated molecular patterns (PAMPs), and/or infectious or noxious insults. The innate immune system relies on protein-protein interactions. The NBDs can bind ribonucleotides, germline-encoded receptors for the detection of microbial sub- possibly regulating self-oligomerization (2, 3). stances or molecules that arise during tissue damage or other sorts Although the NLRs share common features, they differ in of cellular stress. their N-terminal domains. These differences are used to further Several families of innate immune signaling receptors have so subcategorize the NLR protein members (4). The largest group, far been identified. The subcellular location of these receptors var- comprising 14 members, has an N-terminal pyrin domain (PYD) ies substantially and reflects their biological roles. The transmem- and is therefore called “NLRP” (previously also called “NALPs”). brane TLRs and C-type lectin receptors are situated on the plasma Another group, which shares an N-terminal caspase recruitment membrane and on internal membranes (endosome, lysosome, and domain (CARD), contains the proteins nucleotide-binding oligo- endoplasmic reticulum). The cytosol contains the retinoic acid– merization domain–containing 1 (NOD1, also known as NLRC1), inducible gene-I–like helicases (RLRs) and the nucleotide-binding NOD2 (NLRC2), as well as NLR family, CARD domain–contain- domain leucine-rich repeat–containing receptors (NLRs). Together, ing 4 (NLRC4, also known as CARD12 or IPAF). Other NLR family members have an acidic transactivation domain or a baculoviral Conflict of interest: The authors have declared that no conflict of interest exists. inhibitory repeat–like domain, such as NLR family, apoptosis Citation for this article: J. Clin. Invest. 119:3502–3511 (2009). doi:10.1172/JCI40599. inhibitory protein 5 (NAIP5). 3502 The Journal of Clinical Investigation http://www.jci.org Volume 119 Number 12 December 2009 science in medicine Figure 1 Graphical depiction of known inflamma- somes. (A) NLRP1 contains, in addition to the NLR-typical LRR and NBD domains, a PYD, a FIIND, and a CARD. NLRP1 can recruit pro–caspase-1 and -5 and possibly forms a complex with NOD2. Recruitment of ASC enhances activation of pro–caspase-1. (B) NLRC4 contains a CARD that can directly recruit pro–caspase-1. Reports further dem- onstrate a role for ASC and possibly NAIP5 in NLRC4 inflammasome activation. (C) NLRP3 activates pro–caspase-1 via recruitment of ASC. (D) AIM2 is a bipartite protein consisting of a PYD and DNA-binding HIN200 domain and recognizes cytoplasmic double-stranded DNA and assembles the DNA inflammasome with ASC and pro–caspase-1. Several members of the NLR family, including NLRP1, NLRP3, into a 20-kDa (p20) and a 10-kDa (p10) subunit (14). The active and NLRC4 can assemble multimolecular complexes in response enzyme then assembles into two heterodimers of p20 and p10 sub- to various activators, leading to the activation of inflammatory units, containing two active sites (15). caspases. Activated caspase-1 controls the maturation of the Caspase-1 was initially known as IL-1–converting enzyme, since cytokines of the IL-1 family. In analogy to the apoptosome, which its first known substrate, pro–IL-1β, is proteolytically converted activates apoptosis-inducing caspases (5–7), the NLR multimo- into the bioactive cytokine, IL-1β (14). Mature IL-1β is a potent lecular complexes are termed “inflammasomes,” as they control pyrogen with pleiotropic functions including the activation of inflammatory caspases (8, 9). lymphocytes and endothelial cells and the initiation of the acute According to the NLRs involved, the inflammasomes are NLRP1, phase response (16). Due to this repertoire of highly potent pro- NLRP3, or NLRC4. Recently, the protein absent in melanoma 2 inflammatory activities, accidental release of IL-1β would be quite (AIM2, also known as PYHIN4), which belongs to a different pro- deleterious, which explains the development of a complicated tein family (PYHIN), was also reported to assemble an inflamma- mechanism of regulation in mammals. The regulation of IL-1β some (10–13). This review describes the different inflammasomes, secretion